title: CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops.
abstract: BACKGROUND
  Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS.
  
  
  METHODS
  Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes.
  
  
  RESULTS
  Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known 'cholestasis genes' did not demonstrate homozygosity in the LCS patient.
  
  
  CONCLUSIONS
  Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Sohela
authors.initials: S
authors.lastname: Shah
authors.forename: Laura K
authors.initials: LK
authors.lastname: Conlin
authors.forename: Luis
authors.initials: L
authors.lastname: Gomez
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Aagenaes
authors.forename: Kristin
authors.initials: K
authors.lastname: Eiklid
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Michael T
authors.initials: MT
authors.lastname: Mennuti
authors.forename: Randolph P
authors.initials: RP
authors.lastname: Matthews
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics*; D002779:Cholestasis / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics; D005260:Female; D005832:Genital Diseases, Male / Q000235:genetics; D005838:Genotype; D006720:Homozygote; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics*; D007223:Infant; D008201:Lymphangiectasis, Intestinal / Q000235:genetics; D008209:Lymphedema / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D035781:Siblings; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C546964:CCBE1 protein, human; D002135:Calcium-Binding Proteins; D025521:Tumor Suppressor Proteins